Three-dimensional structure of human cytomegalovirus protease

HERPESVIRUSES encode a serine protease 1,2 that specifically cleaves assembly protein 3 . This protease is critical for replication 4 , and represents a new target for antiviral drug design 5 . Here we report the three-dimensional structure of the protease from human cytomegalovirus (hCMV) at 2.27 Å resolution. The structure reveals a unique fold and new catalytic strategy for cleavage. The monomer fold of the enzyme, a seven-stranded β-barrel encircled by a chain of helices that form the carboxy terminus of the molecule, is unrelated to those observed in classic serine proteases such as chymotrypsin and subtilisin. The serine nucleo-phile at position 132 is activated by two juxtaposed histidine residues at positions 63 and 157. Dimerization, which seems to be necessary for activity 6,7 , is observed in the crystals. Correlations of the structure with the sequences of herpesvirus proteases 1,5,8 suggest that dimerization may confer specificity and recognition in substrate binding.